Spiroindolinones and Therapeutic Uses Thereof

Abstract

Small molecules comprised of spiroindolinone analogues are provided. Some spiroindolinones are provided with a particular relative stereochemistry in which the indolone carbonyl and all three hydrogens are on the same face of the central pyrrolidine ring. A stereoselective method of synthesis is provided for making some of the spiroindolinones described above. Formulations and medicaments are also provided that are directed to the treatment of disease, such as, for example, fungal infections. Therapeutics are also provided containing a therapeutically effective dose of one or more small molecule compounds, present either as pharmaceutically effective salt or in pure form, including, but not limited to, formulations for oral, intravenous, or intramuscular administration.

Description

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH[0001]This invention was made with Governmental support under Grant No. 1R01 Al099190 awarded by the National Institute of Health. The government has certain rights in the inventionFIELD OF THE INVENTION[0002]The invention is generally directed to spiroindolinone-containing small molecules and pharmaceutically acceptable salts thereof, methods of manufacturing such small molecules, and methods for the treatment of fungal or microbial disorders using such therapeutics.BACKGROUND[0003]Candida sp account for 80% of major systemic fungal infections. (Revankar, S. G.; Sobel, J. D., Eds. Candidiasis (Invasive). Merck Manual, 2014) The mortality rate for invasive candidiasis has been estimated around 40%. (Ahmadi, A., et al. JRSM Open 2014, 5, 1-10) Azoles remain a first-line treatment for many systemic fungal infections. All azole antifungal drugs act on the same fungal enzyme 14α-demethylase, but exhibit varying levels of activity against d...

AI Technical Summary

Benefits of technology

The invention is about small molecules called spiroindolinones and their use in making medications. The molecules have certain structures and can be used to treat various disorders. The invention also includes methods for making these molecules and their stereoselective versions. The technical effects of the invention include providing new molecules for the treatment of disorders and methods for their manufacture.

Problems solved by technology

However, there are reports of side effects, including hepatitis, leukopenia, thrombocytopenia, gastrointestinal distress, headache, anaphylaxis and rash.

Moreover, resistance to fluconazole and other azole drugs remains a major problem particularly among immunocompromised patients.

Accordingly, it has not been possible to determine which combination of stereochemical configuration and functional groups are important for biological activity by comparing active compounds with inactive compounds.

Spiroindolinones with a relative stereochemical configuration like those in FIGS. 2b and 4a can not be efficiently synthesized by methods known in the prior art.

2b, with a relative stereochemistry that is correlated with potent antifungal synergy, could not be efficiently synthesized using methods known in the prior art.

However, after a few hours the reaction mixture became cloudy.

It is widely recognized that the average molecular weight and complexity of newly approved oral drugs has been increasing with each year.

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